Insulin/insulin-like growth factor (IGF)s naturally occur in the central nervous system (CNS) and have an important role in cell proliferation and differentiation during brain development and maturation. IGFs, IGF binding protein (IGFBP)s and their receptors are expressed in damaged brain regions suggesting a role for the IGFs system after brain injury. It is now known that neurons can die some hours, even days after an injury. This programmed death is termed delayed neuronal death (DND). The process of DND might provide a therapeutic window of opportunity for insulin/IGFs to reduce brain damage after an insult.
Unilateral hypoxic-ischemic (HI) brain injury was induced using a modified Levine rat model. Intracerebral ventricular (ICV) administration was chosen for the delivery of the peptides. The effects of IGF-1 on neuroprotection were tested when given either before or after the HI insult. The dose response of IGF-1 on neuronal rescue was also determined. The distribution of IGF-1 after HI injury was examined following central administration of 3H-IGF-1. The mode of action of IGF-1 on brain rescue was studied by comparing the treatment effects of IGF-1, IGF-2, des-N-(1-3)IGF-1 (des-IGF-1), insulin, N-terminal tripeptide of IGF-1 (GPE) and (+)-5-Methy1-10,11-dihydro-1H-dibenzo[a,d]cyclo-hepten-5,10-iminemaleare (MK801).
IGF-1 reduced cortical infarction and neuronal loss when given after, but not before, an HI insult in a dose dependent manner. HI brain injury enhanced the penetration of IGF-1 into the brain parenchyma after ICV administration possibly via perivascular pathways and white matter tracks. The effective dose of IGF-I did not alter cortical temperature and serum glucose concentration. Insulin did not alter the outcome at an equimolar dose to IGF-1. The treatment effect of des-IGF-1 was only found at a higher dose. IGF-2 counteracted the treatment effects of IGF-1 on neuronal rescue and tissue uptake of 3H-IGF-1. An equimolar dose of GPE showed a similar response to IGF-1. MK801, an N-methy1-D-aspartate (NMDA) receptor antagonist did not show significant effect in this model.
In summary, IGF-1 was neuroprotective after HI brain injury. The effect of IGF-1 on neuronal rescue depends on the dose and time of delivery. The treatment effect of IGF-1 was independent of hypoglycaemia and hypothermia. The results suggest that this effect is mediated via type one IGF receptors. Distinctive treatment effects by des-IGF-1 and IGF-2 suggested a critical role for IGFBPs on neuronal rescue with IGF-1. A secondary mode of IGF-I action on brain rescue could be through the proteolytic production of GPE. In summary, IGF-1 can improve neuronal outcome in vivo suggesting possible clinic application as a therapeutic agent.